Elevated levels of plasma fibrinogen, the major structural protein of blood clots, are strongly associated with cardiovascular disease. But while fibrinogen fulfills many etiological criteria, it remains unclear whether elevated levels of fibrinogen are an important cause of cardiovascular disease or an effect of it. This link between fibrinogen and cardiovascular disease may lie not only in the level of plasma fibrinogen, but also in its composition. We found that elevated levels of a minor fibrinogen isoform called gamma prime (gammaA/gamma') fibrinogen were associated with coronary artery disease. This observation is consistent with findings from an independent research group, who reported an association between the ratio of gammaA/gamma' fibrinogen to total fibrinogen and arterial thrombosis. To date, however, no study has directly tested the association between gammaA/gamma' fibrinogen and traditional cardiovascular disease risk factors (e.g. smoking, hypertension, diabetes, and cholesterol). Furthermore, the clinical and biochemical properties of gammaA/gamma' fibrinogen implicate it in direct mediation of cardiovascular disease pathogenesis. In this application, we propose three Specific Aims: 1) To determine the distribution of gammaA/gammaA fibrinogen and gammaAgamma' fibrinogen among the Framingham Offspring cohort and investigate gender- and age-specific characteristics. 2) To determine the relationship between fibrinogen isoforms and established cardiovascular disease risk factors. 3) To determine if the fibrinogen isoforms in plasma are independently associated with CVD.